Cell mediated immunity is suppressed during pregnancy. This suppression has the beneficial effect of preventing a cytotoxic response to paternal forms of polymorphic proteins expressed at the maternal/fetal interface. On the other hand, the suppression is also responsible for an increased susceptibility to intracellular pathogens. The mechanisms responsible for initiating the downregulation of cell-mediated immunity have not been determined. Trophoblasts are the only fetal cells in direct contact with maternal tissue, and are the cells which initially invade the maternal endometrium and blood vessels to establish a nutrient source for the growing embryo. It is possible that trophoblasts are also involved in initiating the downregulation of cell-mediated immunity, either by production of locally or systemically active immunosuppressive factors or by serving as defective/anergy-inducing, antigen presenting cells. The studies proposed will evaluate the nature of tolerance to a trophoblast-specific foreign antigen using a transgenic mouse model system. Specifically, the maternal response to HLA-U, a major histocompatibility xenoantigen, expressed on trophoblasts at the maternal fetal interface will be evaluated. Analysis of the maternal response to HLA-G will be simplified by use of T cell receptor transgenic mice in which most T cells express the single T cell receptor encoded by the transgenes. T cell receptor transgenic mice will be produced which carry transgenes encoding a receptor which recognizes HLA-G (G-TCR). The numbers, functional state, cytokine secretion patterns, and accessory molecule expression patterns of the G-TCR expressing lymphocytes will be studied in TCR transgenic mothers carrying HLA-G transgenic and non-HLA-G transgenic embryos. The fate of G-TCR expressing lymphocytes will also be studied in recipients of HLA-G expressing trophoblast grafts, HLA-G expressing spleen grafts, and simultaneous trophoblast and spleen grafts. The goal of these studies is to determine l) whether pregnancy is associated with tolerance to a foreign antigen, and, if so, what the nature of this tolerance is 2) whether induction of maternal tolerance to the antigen requires the presence of that antigen on trophoblast, 3) whether tolerance can be induced by trophoblast grafts implanted outside of trophoblast's natural intrauterine environment, and 4) whether a normally strong stimulator of immunity to the antigen can overcome trophoblast-induced tolerance.